PROJECT SUMMARY/ABSTRACT Despite improved attitudes towards sexual and gender minority (i.e., lesbian, gay, bisexual, transgender, and queer/questioning) youth (SGMY) in the US, sexual orientation and gender identity disparities in substance use are staggering and widening over time. This demonstrates an urgent need to understand who among SGMY are most at risk and the amendable factors that contribute to SGMY substance use. Stymied by data exclusion, measurement limitations, and small sample sizes, researchers have yet to explore critically important sociodemographic and interpersonal factors that exacerbate or attenuate risk for SGMY substance use. As a result, there is little empirical basis for SGMY-focused substance use prevention and intervention strategies, particularly for youth. Most current national studies do not include measures that capture theoretically supported drivers of SGMY health disparities such as stigma and discrimination. Yet, minority-specific mechanisms of substance use could hold the key to developing focused and effective prevention strategies to curtail SGMY substance use. Left unexplored, stakeholders are unable to determine the best avenues to support the most vulnerable among SGMY ethnoracially-diverse young people. This proposal addresses these limitations through a rigorous and systematic secondary data analysis of a newly collected national sample of diverse SGMY ages 13-17 (N = 9,299); the research project was explicitly designed to capture greater ethnoracial, geographic, and socioeconomic diversity, as well as minority-specific experiences in relation to health. Three specific aims are proposed: (1) assess rates of alcohol, tobacco, marijuana, and polysubstance use among SGMY across groups defined by multiple health-relevant demographic characteristics (i.e., sex, sexual orientation, gender identity, and ethnoracial identity), (2) rigorously test the relationships between proximal (i.e., internalized homophobia, expectations of rejection) and distal (i.e., SGMY-specific discrimination and victimization) minority stressors and SGMY substance use, and (3) examine the extent to which family and teacher SGMY-specific support moderate the association between minority stress and substance use for SGMY and whether these effects vary by sex, sexual orientation, gender identity, and ethnoracial identity. We propose a combination of logistic regression models, mediation and multiple-group analyses in a path analysis framework, and latent class analysis to mono- and polysubstance use by sex, sexual orientation, gender identity, and ethnoracial identity. The examination of both risk and protective factors will highlight critical points for policy as well as individual-level prevention strategies to eliminate sexual orientation and gender identity- related disparities in substance use and foster positive development for SGMY. We expect our findings to help progress understanding of SGMY substance use and the amendable factors that contribute to them.